scholarly journals Characterizing Inclusion and Exclusion Criteria in Clinical Trials for CAR-T Cellular Therapy Among Adults with Hematologic Malignancies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5819-5819
Author(s):  
Jordon Jaggers ◽  
Heidi D. Klepin ◽  
Tanya M. Wildes ◽  
Rebecca L. Olin ◽  
Andrew S. Artz ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Research Funding ◽  
Cellular Therapy ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Advisory Board ◽  
Exclusion Criteria ◽  
Car T ◽  
History Of

Introduction: Clinical trial development and enrollment are pivotal to advancing cancer outcomes. Novel treatment modalities such as Chimeric Antigen Receptor (CAR) T-cell therapy is an intensive therapy that has altered the landscape of hematologic malignancy therapies, with several FDA approvals based on Phase I-II studies. Strict eligibility criteria are implemented to ensure safety of trial participants; however, these criteria can lead to barriers to patient enrollment, hinder the generalizability of the study, and result in a population of participants not representative of those who would benefit from therapy. The aim of this proposal is to characterize inclusion and exclusion criteria in clinical trials for CAR-T cellular therapy in adults with hematologic malignancies. Methods: The U.S. National Library of Medicine's Clinical Trial database of privately and publicly funded clinical studies was accessed June 2019 to assemble a list of studies with the following filters applied: hematologic, recruiting, not yet recruiting, not recruiting, active, completed, suspended, terminated studies, interventional studies, CAR, CAR T, chimeric antigen receptor, CAR NK, adult, older adult, early phase 1, phase 1, phase 2, phase 3. From this, 95 studies populated, 84 were utilized in this study and 11 studies excluded due to non-hematologic malignancy. Results: We analyzed 84 CAR-T clinical trials targeting multiple diseases (Table 1) including; acute lymphoblastic (n=7) and myeloid leukemia (n=2); lymphoma (n=6); multiple myeloma (n=40); multiple hematologic malignancies (n=27) and other (n=2). The majority of studies were phase 1 (n=47) or phase 1/2 (n=28). Upper age limit restrictions were in place for 53/84 (63%) of trials. Trials included the AYA population (n=5), ≤ age 65 (n=1), ≤ age 70 or 73 (n=26), ≤ age 75 or 78 (n=12), ≤ age 80 or 85 (n=9). Of the 84 trials, 65 (77%) had performance status inclusion criteria, most commonly was status ECOG 0-2 (n=23) and ECOG 0-1 (n=24). Patients were excluded for a history of a separate or concurrent malignancy in 52/84 (62%) trials, CNS disease was excluded in 45/84 (54%) trials and 70/84 (83%) clinical trials excluded infectious diseases; HIV (n=69) and Hepatitis B/C (n=64). Many studies had restrictions for impairment in organ function; renal impairment (n=66), cardiac deficits (n=67), and abnormal pulmonary function (n=44). Unique to CAR-T trials, 27/84 had restrictions in place for neurological disorders: epilepsy (n=15), history of brain injury (n=10), dementia (n=8), coordination/movement disorder (n=6), cerebellar disease (n=8), psychosis (n=7), paresis (n=6), history of stroke/aphasia (n=21), and active autoimmune or inflammatory disease of the central nervous system (n=3). Conclusion: CAR-T cellular therapy is a tremendous therapeutic advancement in the medical community. This study emphasizes, in detail, highly variable cross-study inclusion/exclusion criteria for early phase CAR-T studies. This new and promising therapy is actively being studied in a highly select group of patients and may not be generalizable to the older adult with hematologic malignancies due to non-uniform trial criteria. The applicability of this modality should be tempered by the understanding that CAR-T trials have overt age caps, ambiguous performance and comorbidity exclusions, and neurologic exclusions and play a role in limiting patient accessibility to novel clinical trial therapy. Confirmatory prospective and observational studies of CAR-T therapy in representative populations are a high priority. 1. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. 2016 127:3321-3330. Doi: 10.1182/blood-2016-04-703751 2. Kim ES, Bruinooge SS, Roberts S, et al. Broadening Eligibility Criteria to Make Clinical Trials More Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement. J Clin Oncol. 2017;35(33):3737-3744. doi:10.1200/JCO.2017.73.7916 3. Unger JM, Cook E, Tai E, and Bleyer A. The Role of Clinical Trial Participation in Cancer Research: Barriers, Evidence, and Strategies. American Society of Clinical Oncology Educational Book. 2016; 36:185-198. Doi:10.1200/EDBK\_156686 Disclosures Wildes: Janssen: Research Funding; Carevive: Consultancy. Olin:Spectrum: Research Funding; Novartis: Research Funding. Artz:Miltenyi: Research Funding. Jaglowski:Unum Therapeutics Inc.: Research Funding; Kite: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Novartis: Consultancy, Other: advisory board, Research Funding. William:Guidepoint Global: Consultancy; Defined Health: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy. Rosko:Vyxeos: Other: Travel support.

scholarly journals Disparity in Clinical Trial Opportunities for Patients with B-Cell Malignancies in the United States

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4861-4861
Author(s):  
Sikander Ailawadhi ◽  
Sri Lekha Bodepudi ◽  
Zan Tahir Shareef ◽  
Fabiola Coromoto Cardozo ◽  
Salman Ahmed ◽  
...  
Keyword(s):  
United States ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Geographical Distribution ◽  
Research Funding ◽  
Phase 1 ◽  
The United States ◽  
Phase 2 ◽  
B Cell Malignancies ◽  
The Us

Abstract Background: Clinical trials are fundamental to advance therapeutics systematically and improve patient outcomes. Despite this, enrollment on clinical trials remains dismal in the United States (US) and is a constant focus of healthcare policy. We studied distribution of clinical trials for B-cell malignancies over time across the US and unique clinical trial opportunities i.e. individual clinical trials for the given diagnosis at a site that patients may have access to participate. Methods: We abstracted data from clinicaltrials.gov for all trials that had non-Hodgkin lymphoma (NHL) or multiple myeloma (MM) as an inclusion indication between 1999-2018. Clinical trial characteristics and distribution over US geographical divisions (West, Midwest, Northeast, and South) were studied, and differences were assessed by Chi-square test. Results: A total of 1930 trials were identified (NHL: 982, MM: 948), of which 483 were recruiting at the time of data abstraction (NHL: 250, MM: 233). Over the past 2 decades, 182691 patients were enrolled on the various trials (NHL: 81592, MM: 101099). Trials by phase of study included phase 1: 629, phase 1/2: 316, phase 2: 813, phase 2/3: 11 and phase 3: 161. Number of trials by phase separated by NHL and MM are shown in Figure 1. Of these, 197 trials were randomized (NHL: 67, MM: 130). Geographical distribution of trials by diagnosis type is shown in Figure 2. A total of 31806 unique trial opportunities were noted for MM and NHL, of which 9,513 were international and 22,293 were in the US, with a geographical distribution of 5080 in West, 8198 in Midwest, 3944 in Northeast, and 5071 in South. 4,883 of the unique trial opportunities were available at NCI/NCCN accredited sites and 17,410 were at non-NCI/NCCN sites in the US. Treatment characteristics of the trials included monoclonal antibodies in 1218, other targeted agents in 2641, stem cell transplant in 526, and other agents in 517 trials with several trials utilizing more than one of these therapeutic options. There was no statistically significant difference in the distribution of clinical trials by phase of study across various US geographical regions for MM (p=0.71), NHL (p=0.98) or combined MM+NHL (p=0.16). On the other hand, unique trial opportunities were significantly different by study phase and geographical distribution for MM, NHL or MM+NHL (all p<0.001) (Figure 3). Conclusions: Widespread access to clinical trials within a cancer diagnosis is imperative for generalizability of trial results. In a comprehensive, national analysis we noted that while it may appear that clinical trials are available across the US, sites where they are open are distributed unevenly, giving rise to a disparity in access to evidence-based therapeutic advancements for patients. Disclosures Ailawadhi: Janssen: Consultancy; Amgen: Consultancy; Pharmacyclics: Research Funding; Takeda: Consultancy; Celgene: Consultancy. Sher:Affimed: Research Funding.

scholarly journals Potential Barriers to Clinical Trials of New Therapeutics for Myelodysplastic Syndromes: Wide Variation in Risk Definitions and Trial Enrollment Criteria

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4378-4378
Author(s):  
Andrew M. Brunner ◽  
Jacqueline S. Garcia ◽  
R. Coleman Lindsley ◽  
Gregory A. Abel ◽  
Donna S Neuberg ◽  
...  
Keyword(s):  
Clinical Trials ◽  
High Risk ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Research Funding ◽  
Phase 1 ◽  
Phase Iii ◽  
Pharmacological Intervention ◽  
Exclusion Criteria ◽  
Very High

Abstract Introduction: Myelodysplastic syndromes (MDS) are neoplasms characterized by cytopenias, high risk of leukemic progression, and poor overall survival. Chemotherapy for MDS is not curative, and no new drugs have been approved for the treatment of MDS in over a decade. Clinical trials should be considered at any time during the management of patients with MDS, but enrollment criteria may be barriers that limit accrual. In this study, we extracted MDS clinical trial data from clinicaltrials.gov, and compared study indications and characteristics, including inclusion and exclusion criteria. Methods: We identified MDS clinical trials via clinicaltrials.gov (accessed: April 16, 2018). Studies were included if they allowed "MDS," "Myelodysplastic syndromes," "Preleukemia," and/or "Myelodysplasia," based on the pre-defined 'related terms' criteria in the database. We included interventional studies open in the United States that were listed as recruiting or not yet recruiting, for adults (age 18-64) and older adults (age 65+). We excluded studies that were observational in nature, involved a transplant-based intervention, or did not use a pharmacological intervention. We coded inclusion and exclusion criteria based on those provided by study authors in the database. Results: 83 interventional clinical trials enrolling patients with MDS were identified. Studies started enrollment between 4/1/2013 and 3/27/2018, and anticipated reaching the primary objective between 5/1/2017 and 6/1/2025. The median planned study duration was 38 mo (range 10-95). In total, studies sought to enroll 8866 patients over 273 study-years; the median study enrollment estimate was 1.7 patients/month, or across all trials 247 patients/month. Clinical trials could be exclusive to MDS patients (n=28), include MDS patients and other myeloid malignancies e.g. AML (n=44), or include MDS patients and other cancers including solid tumors (n=11). For clinical trials exclusive to MDS, the total enrollment goal was 1966 patients over 96 study-years, with a median rate of 1.4 patients/month (range 0.3-13.2) or total of 63 patients/month across all studies. 33 trials were phase 1 studies, 17 were phase 1/2, 26 were phase II, 1 trial was phase 2/3, and 6 were phase III studies. The primary endpoint was typically MTD (n=50) or ORR (n=22), while 5 studies had an OS endpoint. Most trials specified "higher risk" MDS (n=44); 8 specified "lower risk" MDS and 31 allowed all MDS risk or did not specify risk (Figure 1). Lower risk MDS studies were all exclusive to MDS patients. Inclusion criteria related to MDS risk varied significantly according to whether a study was MDS-specific or not (p=0.021): 82% of MDS-specific trials had risk exclusions, compared to 72% of myeloid trials, and only 36% of trials open across cancers. Of 52 trials specifying MDS risk, 20 included IPSS criteria, 24 included IPSS-R criteria, and 27 had blast count criteria. Lower risk MDS criteria was variably defined as IPSS low or INT-1 disease (n=3), IPSS-R very low or low risk (n=1), IPSS-R VL, L, or intermediate risk (n=4), or blast counts < 5% (n=1), < 10% (n=2), or <20% (n=2). There were variations in the criteria for transfusion dependence, including 2 transfusion units in 8 weeks (n=3), 4 in 8 weeks (n=2), 2 in 4 weeks (n=2), 1 in 6 weeks (n=1), and 2 in 16 weeks (n=1). For higher risk MDS, criteria included IPSS INT-1, INT-2, or High risk (n=7), IPSS INT-2 or High risk (n=12), IPSS-R intermediate, high, or very high risk (n=12), or IPSS-R high or very high (n=9); blast counts were set at >5% (n=12) or >10% blasts (n=12). Most studies specified exclusion of CNS disease, even though CNS involvement is exceptionally rare in MDS. 43 trials excluded concurrent cardiovascular disease; most often (n=18) requiring 6mo since a cardiovascular event. 46 trials had language excluding concurrent cancers, including 4 that did not allow any prior cancer, and 17 required ³24mo disease free. Exclusions for prior cancers did not vary according to primary outcome (MTD or PK, vs ORR/OS, p=0.16). 20 of 56 studies with MTD or early outcomes (e.g. PK) required cancer-free intervals of ³1y, while 7 allowed concurrent cancers if not on active therapy. Discussion: Currently enrolling MDS clinical trials show significant variation in their inclusion and exclusion criteria. Heterogeneous definitions of basic entry criteria, such as the definition of higher- and lower-risk MDS, may cause barriers to enrollment. Disclosures Brunner: Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Garcia:Celgene: Consultancy.

scholarly journals The Relationship between Depression, Anxiety, and Clinical Trial Perceptions Among Patients with Hematologic Cancer

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1901-1901
Author(s):  
Kimberly Papay Rogers ◽  
Victoria G. Morris ◽  
Melissa F. Miller ◽  
Thomas W. LeBlanc
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Research Funding ◽  
Clinical History ◽  
Advisory Board ◽  
Anxiety And Depression ◽  
Hierarchical Regression ◽  
Depression And Anxiety ◽  
Hematologic Cancer ◽  
The Relationship

Abstract Introduction. Despite the fact that thousands of cancer clinical trials (CCTs) are available today, engagement remains low, with only 2-7% of patients with cancer participating in CCTs. Research has shown that this may partially be due to fear-based perceptions around CCTs. Unfortunately, depression and anxiety, two psychological factors that are highly prevalent in the cancer space, are known to bias attention in ways that alter perceptions and are specifically known to amplify fear-based perceptions. Thus, the purpose of this exploratory study was to examine the relationship between depression, anxiety, and perceptions of clinical trials among patients with hematologic cancer. Method: In this observational, cross-sectional study, 625 patients with hematologic cancer (46.4% multiple myeloma; 19.5% CLL; 11.4% non-Hodgkin lymphoma; 4.0% AML; 3.5% Hodgkin lymphoma; 3.2% CML; 1.6% ALL; 1.3% MPN; 7.4% other lymphoma; 1.8% other leukemia) completed the Cancer Support Community's online survey, the Cancer Experience Registry®. Participants provided sociodemographic and clinical history information, rated their level of agreement (0 = strongly disagree to 4 = strongly agree) with 8 statements related to beliefs about CCTs, and completed the Anxiety and Depression subscales (4 items each rated 1 = never to 5 = always) from the Patient-Reported Outcomes Measurement Information System (PROMIS-29v2.0). Responses to these 8 PROMIS items were averaged to compute a combined depression and anxiety score on a 5-point Likert scale. To understand the impact of depression and anxiety on perceptions of CCTs, 8 hierarchical regression models were examined; the dependent variable for each model was one of the CCT perception variables. Clinical history (cancer diagnosis, time since diagnosis, type of cancer care facility) and sociodemographic variables (age, gender identity, income, educational attainment, race, ethnicity, geographic area) were controlled for. Results: The sample was 54.9% female, 86.7% Non-Hispanic White, 60.1 years old on average (SD=10.8) and had an average time since diagnosis of 5.3 years (SD=5.3; Median = 3.0 years; IQR = 6 years). 67.7% had a college degree, 20.5% had a gross annual household income of $100,000 or above, 41.4% received cancer treatment at an academic or comprehensive cancer center, and 45.6% lived in a suburban area. Participants' average anxiety and depression score was 1.91 (SD=.93). Hierarchical regression analyses demonstrate that depression and anxiety had a significant effect on 7 of the 8 CCT perceptions assessed, when controlling for sociodemographic and cancer characteristics. Specifically, depression and anxiety were significant predictors of participants' perceptions that, "I would be unable to fulfill trial requirements due to logistical barriers" (ΔR 2=.019, b=.19, p=.003), "I don't trust the medical establishment and fear I will be used as a 'guinea pig'" (ΔR 2=.017, b=.17, p=.006), "I am uncomfortable with being randomly assigned" (ΔR 2=.016, b=.19, p=.01), "I fear receiving a placebo (for example, a sugar pill) in a clinical trial" (ΔR 2=.012, b=.18, p=.024), "I don't understand what clinical trials are" (ΔR 2=.011, b=.13, p=.021), "There are no clinical trials available in my community" (ΔR 2=.010, b=.14, p=.030), and "I fear side effects that might come with treatment on a clinical trial" (ΔR 2=.009, b=.13, p=.047). Thus, depression and anxiety accounted for significant amounts of variance in each of these clinical trial perceptions above and beyond the controls. Depression and anxiety did not have a significant impact on participants' perceptions that their health insurance would not cover a CCT (ΔR 2=.002, b=.05, p=.370). Conclusion. Our findings demonstrate small but significant relationships between depression, anxiety, and perceptions of CCTs among patients with hematologic cancer. While common attempts to alter CCT perceptions often focus on information dissemination, the present study indicates that psychological factors may also need to be considered. While this study is an important first step in considering the relationship between mental health and perceptions of CCT, further longitudinal research is needed to better elucidate these findings. For example, differential analyses should explore if and how these relationships differ among patients with pre-existing clinically-significant levels of depression and anxiety. Disclosures LeBlanc: AbbVie: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; Flatiron: Consultancy, Other: Advisory board; AstraZeneca: Consultancy, Honoraria, Other: Advisory board, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria, Other: Advisory board; UpToDate: Patents & Royalties; Pfizer: Consultancy, Other: Advisory Board; CareVive: Consultancy, Other, Research Funding; NINR/NIH: Research Funding; Helsinn: Consultancy, Research Funding; Agios: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; Astellas: Consultancy, Honoraria, Other: Advisory board; Seattle Genetics: Consultancy, Other: Advisory board, Research Funding; Jazz Pharmaceuticals: Research Funding; Otsuka: Consultancy, Honoraria, Other; BMS/Celgene: Consultancy, Honoraria, Other: Travel fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Other: travel; Heron: Consultancy, Honoraria, Other: advisory board; American Cancer Society: Research Funding; Duke University: Research Funding.

scholarly journals Ivosidenib (AG-120) Induced Durable Remissions and Transfusion Independence in Patients with IDH1-Mutant Relapsed or Refractory Myelodysplastic Syndrome: Results from a Phase 1 Dose Escalation and Expansion Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1812-1812 ◽  
Author(s):  
Courtney D. DiNardo ◽  
Justin M. Watts ◽  
Eytan M. Stein ◽  
Stephane de Botton ◽  
Amir T. Fathi ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Advisory Board ◽  
Employment Equity ◽  
Transfusion Independence ◽  
Starting Dose ◽  
Equity Ownership ◽  
Advisory Role

Abstract BACKGROUND: Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) are observed in approximately 4% of patients with myelodysplastic syndrome (MDS) and have been linked with increased transformation to acute myeloid leukemia. Ivosidenib (AG-120), an oral, potent, targeted, small-molecule inhibitor of the mutant IDH1 protein (mIDH1), is a therapeutic candidate for the treatment of patients with mIDH1 MDS. Through inhibition of mIDH1, ivosidenib suppresses the production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from patients with relapsed or refractory (R/R) MDS enrolled in the first-in-human, phase 1, dose escalation and expansion study of ivosidenib in patients with mIDH1 advanced hematologic malignancies (NCT02074839). METHODS: This ongoing study is evaluating the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Trial enrollment was completed on 08May2017. In dose escalation, patients received single-agent ivosidenib orally once daily (QD) or twice daily in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the dose to be tested in expansion. Expansion Arm 3 enrolled patients with mIDH1 advanced hematologic malignancies, including MDS. The overall response rate (ORR) for MDS was defined as complete remission (CR) + partial remission + marrow CR. Exploratory biomarker assessments included baseline co-occurring mutations (next-generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02-0.04%). Here, we present safety and efficacy data for patients with MDS in expansion Arm 3 and in dose escalation whose starting dose was 500 mg QD. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) received ivosidenib, including 12 patients with MDS (9 from expansion and 3 from escalation) whose starting dose was 500 mg QD. Baseline characteristics for these 12 patients were: 9 men/3 women; median age, 72.5 years (range, 52-78) and 42% were ≥75 years of age; median number of prior therapies, 1 (range, 1-3). As of 10Nov2017, 7 of 12 (58.3%) patients remained on treatment and 5 (41.7%) had discontinued (one for allogeneic stem cell transplantation). The median duration of exposure to ivosidenib was 11.0 months (range, 3.3-31.1). The most common adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were back pain (n=4, 33.3%) and anemia, decreased appetite, diarrhea, dyspnea, fatigue, hypokalemia, pruritus, and rash (n=3, 25.0% each). The majority of these AEs were grade 1-2 and reported as unrelated to treatment. No AEs led to permanent discontinuation of treatment. IDH differentiation syndrome (IDH-DS) was observed in 2 of 12 (16.7%) patients; the events were grade 1 and 2, respectively. Of the 12 patients with MDS receiving ivosidenib 500 mg QD, 5 achieved CR (41.7%; 95% CI 15.2%, 72.3%) and 6 achieved marrow CR (50.0%), resulting in an ORR of 91.7% (95% CI 61.5%, 99.8%). The median durations of CR and overall response were not estimable at the time of the data cutoff. The percentages of patients who remained in CR and response at 12 months were 60.0% and 61.4%, respectively. Among 5 patients who were transfusion dependent at baseline, 4 became transfusion independent for at least 56 days on treatment. Baseline co-occurring mutations and changes in mIDH1 VAF levels on ivosidenib therapy will be presented. CONCLUSION: In patients with mIDH1 R/R MDS, ivosidenib monotherapy was well tolerated and induced durable remissions and transfusion independence. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS. Disclosures DiNardo: Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Watts:Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Stein:Celgene: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Bayer: Consultancy. de Botton:Agios: Research Funding; Celgene: Honoraria, Research Funding. Fathi:Takeda: Consultancy, Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Agios: Honoraria, Research Funding. Stein:Amgen: Speakers Bureau; Celgene: Speakers Bureau. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Stone:AbbVie: Consultancy; Agios: Consultancy, Research Funding; Cornerstone: Consultancy; Orsenix: Consultancy; Fujifilm: Consultancy; Sumitomo: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Ono: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Jazz: Consultancy; Merck: Consultancy; Astellas: Consultancy; Arog: Consultancy, Research Funding; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy. Patel:France Foundation: Honoraria; Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tallman:Cellerant: Research Funding; BioSight: Other: Advisory board; ADC Therapeutics: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Orsenix: Other: Advisory board. Choe:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Kapsalis:Agios: Employment, Equity Ownership. Hickman:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership, Patents & Royalties. Attar:Agios: Employment, Equity Ownership.

A Phase 1 Trial of Oral Ponatinib (AP24534) In Patients with Refractory Chronic Myelogenous Leukemia (CML) and Other Hematologic Malignancies: Emerging Safety and Clinical Response Findings

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 210-210 ◽  
Author(s):  
Jorge Cortes ◽  
Moshe Talpaz ◽  
Dale Bixby ◽  
Michael Deininger ◽  
Neil Shah ◽  
...  
Keyword(s):  
Research Funding ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Advisory Board ◽  
Recommended Dose ◽  
Molecular Response ◽  
Tablet Form ◽  
Phase 1 Trial ◽  
Hematologic Response ◽  
T315i Mutation

Abstract Abstract 210 Background: Despite progress in CML therapy, patients (pts) who fail 2 or more tyrosine kinase inhibitors (TKI), or pts with T315I mutation, have no available treatment options. Ponatinib (AP24534), an oral multiple TKI, is a potent pan-BCR-ABL inhibitor with activity against all tested imatinib-resistant mutants, including T315I. It also inhibits other kinases, including FLT3. Methods: An ongoing, open-label, dose escalation, phase 1 trial aims to assess the safety of ponatinib, establish a recommended dose, and investigate anti-leukemic activity. Pts with refractory hematologic malignancies were enrolled to receive a single daily dose of ponatinib in capsule or tablet form. Results: As of July 16, 2010, 67 pts (55% males) were enrolled: median age, 58 (range 26–85) years; median time from initial diagnosis to start of ponatinib, 5.2 (range 0–21) years. Diagnoses included 57 CML (42 chronic [CP], 7 accelerated [AP], 8 blast phase [BP]), 3 Ph+ acute lymphoblastic leukemia (ALL), 3 acute myeloid leukemia (AML), and 4 other hematologic malignancies. Prior therapies in CML/Ph+ pts included imatinib (96%), dasatinib (89%), nilotinib (55%); 95% and 64% failed ≥2 and ≥3 prior TKIs, respectively; 72% had BCR-ABL mutations at study entry or documented history, including 23 (38%) T315I, and 7 (12%) F317L. At the time of reporting, pts were treated at doses up to 60 mg, 43 (64%) pts remained on therapy, 24 (36%) discontinued: 8 (12%) progressive disease; 8 (12%) investigator decision; 5 (8%) unrelated deaths; 2 (3%) consent withdrawn; 1 (2%) unrelated adverse event (AE), CNS bleed. The most common drug-related AEs (≥10% any grade) were thrombocytopenia (24%), headache (14%), nausea (14%), arthralgia (13%), fatigue (13%), anemia (11%), increased lipase (11%), muscle spasms (11%), rash (11%), myalgia (10%), and pancreatitis (10%). At 60 mg, elevation of pancreatic enzymes and pancreatitis were dose-limiting toxicities (DLTs) in 4/14 treated pts. To date, 1/22 pt treated at 45 mg had a DLT (grade 3 rash). All DLTs were reversible. Overall, 48 Ph+ pts were evaluable for response (at least 1 response assessment). Of 32 evaluable CML CP pts, 30 (94%) had complete hematologic response (CHR), and 20 (63%) had major cytogenetic response (MCyR): 12 complete CyR (CCyR), 8 partial CyR (PCyR). Of 20 CML CP cytogenetic responders, 18 remain on treatment (mean duration 326 [range 142–599] days) without progression, 13 of whom had response confirmed with at least a second assessment (9 with MCyR ≥6 months), and 2 pts treated at 4 and 15 mg progressed after PCyR. Of 11 CML CP pts with T315I mutation, 11 (100%) had CHR, 9 (82%) had MCyR (8 CCyR). For 16 evaluable CML AP/BP or Ph+ ALL pts, 5 (31%) had major hematologic response (MHR), 3 (19%) had MCyR, 1 (6%) had minor CyR. Of 9 CML AP/BP or Ph+ ALL pts with T315I mutation, 3 (33%) had MHR, 2 (20%) had MCyR. Responses were also observed in heavily refractory pts with no mutations, and pts with other mutations, who are resistant to approved TKIs: 1 CCyR and 1 PCyR in 2 F317L pts who each failed imatinib, dasatinib, and nilotinib; a F359C pt who failed imatinib and nilotinib had CHR and CCyR. Overall, 13/60 (22%) Ph+ pts achieved major molecular response (MMR), including 12/42 (28%) CP pts, 6/15 (40%) with T315I mutation confirmed at baseline, 10/40 (25%) with starting doses ≥30 mg. 12 MMRs occurred in pts who were on treatment '4 months (4 MMRs ≤2 months). MMRs were also achieved in pts with M351T, F359C, F317L, M244V, G250E mutations, and 1 pt with no mutation. PD data demonstrate sustained inhibition of CrkL phosphorylation above 15 mg. Evaluation of ponatinib tablets began in April 2010 with intent to transition from capsules to tablets for future studies. To date, 10 pts received ponatinib tablets: n=9, 45 mg; n=1, 60 mg. Initial safety, PK/PD, and molecular response data suggest both dosage forms behave similarly. Importantly, at doses ≥30 mg, both result in trough concentrations >40 nM—the target concentration for inhibiting all BCR-ABL mutants, including T315I. Conclusion: ponatinib has an acceptable safety profile at clinically effective doses in this refractory population. The 45 mg dose (tablet form) was chosen as the recommended dose for further study. There is strong and continually increasing evidence of anti-leukemic activity in pts with T315I mutations, and pts resistant to second generation TKIs. Emerging MMR data demonstrate early responses in pts refractory to second line agents. Disclosures: Cortes: ARIAD: Research Funding; Chemgenex: Research Funding; Deciphera: Research Funding. Talpaz:Novartis: Honoraria. Deininger:ARIAD: Advisory Board, Consultancy, Honoraria; Novartis: Advisory Board, Consultancy, Honoraria; BMS: Advisory Board, Consultancy, Honoraria; Genzyme: Research Funding. Shah:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy. Flinn:ARIAD: Research Funding. Hu:ARIAD: Employment. Kan:ARIAD: Employment. Rivera:ARIAD: Employment. Clackson:ARIAD: Employment. Haluska:ARIAD: Employment. Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding.

scholarly journals Impact of Prior Cancer on Eligibility for Plasma Cell Disorder (PCD) Clinical Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2267-2267
Author(s):  
Sandra Garcia ◽  
Olivia Dorsey ◽  
Sandi Pruitt ◽  
Saurabh Dahiya ◽  
David Gerber ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Research Funding ◽  
Exclusion Criterion ◽  
Exclusion Criteria ◽  
Advisory Committees ◽  
History Of ◽  
Plasma Cell Disorder ◽  
Cancer Trials

Abstract History of prior cancer is a widespread exclusion criterion in cancer trials. Up to 80% of NCI-sponsored and 80% of industry-sponsored lung cancer trials exclude patients with a prior cancer. We suspect this exclusion is commonly applied in other cancer trials, although no definitive data exist. Prior cancer is especially common among older patients and those with certain cancer types. Among patients >65 years, 15.1% overall have prior cancer. In Multiple Myeloma, the most common plasma cell disorder (PCD), prevalence of prior cancer is as high as 17.4%. Examining the prior cancer exclusion criterion is important because the number of US cancer survivors is large and rapidly growing. Arbitrarily excluding cancer survivors from trials is not evidence-based and exclusion presumably arises from assumptions that higher mortality of patients with prior cancer could hinder study conduct and bias trial outcomes. However, few data exist to support this assumption of higher mortality. In fact, we demonstrated that lung cancer patients with a prior cancer have similar or lower mortality risk, compared to those without prior cancer. In this abstract, we reviewed prior cancer related eligibility criteria in three of the most common PCD (Multiple Myeloma, Amyloidosis and Waldenström Macroglobulinemia) clinical trials sponsored or endorsed by 5 major Co-Operative groups in North America (Table 1). We use descriptive statistics (n, %) and Fisher's exact tests to describe characteristics of trials with and without exclusion criteria. Of 33 trials, 26 (79%) excluded patients with prior cancer as follows - active cancer (12%), within 2-3 years of PCD diagnosis (9%), or within 5 years of PCD diagnosis (55%). Many trials had exceptions to prior cancer exclusion. Specifically, 67% of trials allowed non-melanoma skin cancer, 58% allowed in-situ cervical cancer, 12% allowed early stage prostate cancer. Table 2 shows the association between clinical trial characteristics and prior cancer exclusion. There was no association between prior cancer exclusion and phase of study, transplant studies, or survival end point. Exclusion criteria varied across year of activation (p=0.01); for example, 75% of studies activated 1990-1999 excluded prior cancer, compared to 100% of studies activated after 2010. Type of PCD was marginally associated with exclusion criteria (p=0.08); 74% of Multiple Myeloma trials excluded patients with prior cancer compared to 100% of the Amyloidosis and Waldenström Macroglobulinemia trials. Conclusion: A substantial proportion of potential participants may be excluded from PCD clinical trials because of a history of prior cancer. This practice impacts accrual, generalizability, and fair access to cutting-edge treatments and the highest level of clinical care. As treatment outcomes for other cancers continue to improve, it is likely that the prevalence of multiple primary cancers will increase. This exclusion criterion is applied widely across studies, including more than two-thirds of those with non-survival endpoints. Our study is the first to examine the prevalence and potential impact of prior cancer exclusion in PCD clinical trials. Using population-based cancer registry data, we plan to undertake further research to understand the appropriateness and ramifications of this standard exclusion policy in PCD cancer trials. Disclosures Collins: Agios: Research Funding; Bristol Myers Squibb: Research Funding; Celgene Corporation: Research Funding; Arog Pharmaceuticals: Research Funding. Devine:Kiadis Pharma: Consultancy. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy. Anderson:Amgen: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Kumar:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Prevalence of Familial Plasma Cell Disorders in Patients with Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-2
Author(s):  
Alissa Visram ◽  
Eli Muchtar ◽  
S. Vincent Rajkumar ◽  
Celine M. Vachon ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Family History ◽  
Plasma Cell ◽  
Research Funding ◽  
Advisory Board ◽  
Cox Proportional Hazards Model ◽  
Degree Relative ◽  
Plasma Cell Disorders ◽  
History Of ◽  
Second Degree

Introduction: First degree relatives of patients with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM), and African Americans, have an increased risk of having MGUS and MM compared to the general population. However, current guidelines do not advocate for screening family members of MM for plasma cell disorders (PCD). Understanding the epidemiology of familial plasma cell disorders (PCDs) is essential in order to identify people at highest risk of developing PCDs who may benefit from targeted screening strategies. The aims of this study were to assess the prevalence of MM patients with a family history of PCD, and the implications of a family history of PCD on the overall survival (OS) of MM patients. Methods: We retrospectively reviewed the electronic medical records of patients with symptomatic MM followed at Mayo Clinic and diagnosed between January 1989 and June 2019. Clinical notes were reviewed for documentation pertaining to family history of PCDs. Kaplan Meier survival analysis was used to assess the OS, where OS was calculated from the date of diagnosis of symptomatic MM until death; patients were censored if they were alive at the date of last follow up. A Cox proportional hazards model was used to provide risk estimates for OS. Results: A total of 8403 patients with symptomatic MM were included in this study. Family history was documented in 1521 patients, and 291 patients (3.5% of all patients, 19% of those with any documented family history) had a documented family member with a PCD. The median age at diagnosis of symptomatic MM was significantly lower in patients with (n=291) versus without (n= 8112) a family history of PCD (60.9 versus 63.6 years, p&lt;0.0001). The median OS of MM patients with a family history of PCD was significantly longer than MM patients without a family history of PCD (8.1 versus 4.9 years, respectively, with p&lt;0.0001, see figure 1). Using a multivariable Cox proportional hazards model, MM patients with a family history of PCD had a significantly lower risk of death compared to those without a family history of PCD (HR 0.66, 95% CI 0.55-0.78, p&lt;0.0001) even after adjusting for sex, age at diagnosis (above versus below age 65), self-reported race (African American versus not African American), or date of diagnosis (before versus after 2010). When restricting the analyses to the 1521 patients with clearly documented family history, the survival benefit amongst patients with versus without a family history of PCD was similar. In probands with a PCD family history, 182 (63%) had a first degree relative with PCD, whereas 109 (37%) had a second degree relative with PCD. The most common reported PCD amongst family members was MM (figure 2). Nineteen (6.5%) probands with a family history of PCD had 2 or more relatives with a PCD (6 MM patients had 2 or more first degree relatives, 5 MM patients had at least 1 first and 1 second degree relative, and 8 MM patients had 2 or more second degree relatives with a PCD history). There was no significant difference in the median OS between MM patients with a first degree versus second degree relative with PCD (HR 1.03, 95% CI 0.74-1.46, p=0.837), or MM patients with 1 versus 2 or more relatives with PCD (HR 1.01, 95% CI 0.53-1.96, p=0.962). Conclusion: We reviewed patients with symptomatic MM seen at Mayo Clinic over the last 30 years and found that the prevalence of patients with a documented family history of PCD was 3.5%. MM patients with a family history of PCD were diagnosed with MM at a younger age and survived longer than patients without a family history of PCD. Further work is needed to understand factors underlying the survival benefit in patients with a family history of PCD, and whether they present with less aggressive or less advanced disease at diagnosis. Disclosures Dispenzieri: Intellia: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Kapoor:Sanofi: Consultancy, Research Funding; Cellectar: Consultancy; Janssen: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Honoraria. Gertz:Spectrum: Other: personal fee, Research Funding; Janssen: Other: personal fee; Abbvie: Other; Amgen: Other: personal fee; Physicians Education Resource: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau; Prothena: Other: personal fee; Teva: Speakers Bureau; Celgene: Other; Research to Practice: Other; Sanofi: Other; DAVA oncology: Speakers Bureau; Annexon: Other: personal fee; Appellis: Other: personal fee; Ionis/Akcea: Other: personal fee; Alnylam: Other: personal fee; Aurora Bio: Other; Proclara: Other; Johnson and Johnson: Speakers Bureau; Springer Publishing: Patents & Royalties. Kumar:Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Carsgen: Other, Research Funding; Cellectar: Other; Dr. Reddy's Laboratories: Honoraria; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Sanofi: Research Funding; Tenebio: Other, Research Funding; Kite Pharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Genecentrix: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments.

scholarly journals Aggressive Smoldering Curative Approach Evaluating Novel Therapies (ASCENT): A Phase 2 Trial of Induction, Consolidation and Maintenance in Subjects with High Risk Smoldering Multiple Myeloma (SMM): Initial Analysis of Safety Data

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-36
Author(s):  
Shaji K. Kumar ◽  
Al-Ola Abdallah ◽  
Ashraf Z. Badros ◽  
Betsy Laplant ◽  
Binod Dhakal ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
High Risk ◽  
Research Funding ◽  
Advisory Board ◽  
Phase 2 ◽  
Phase 3 ◽  
Phase 2 Trial ◽  
Risk Of Progression ◽  
M Spike

Background: Smoldering multiple myeloma (SMM) represents an intermediate stage between monoclonal gammopathy of undetermined significance and active myeloma with a high risk of progression to active MM, especially during the initial years after diagnosis. Available clinical risk factors have enabled development of risk stratification systems that allow for identification of patients at the highest risk of progression, opening opportunities for early intervention. Two phase 3 trials using lenalidomide with dexamethasone or lenalidomide alone have both shown benefit for early intervention by decreasing the risk of progression and improving the overall survival in the former. It remains unknown if an approach using a single active drug to delay progression, or one that uses therapies like active myeloma, represent a better approach; both are being studied in phase 3 trials. We designed this phase 2 trial to examine if an intense but limited duration therapy can possibly provide a significant elimination of the tumour burden that can potentially lead to long term responses. Patients and Methods: Patients with SMM (per updated IMWG definition of SMM) with high risk disease (defined by the IMWG updated risk stratification criteria- presence of any two of the following: Serum M spike &gt; 2 gm/dL OR an involved to uninvolved FLC ratio &gt; 20 OR bone marrow PC% &gt; 20%) or a score of ≥9 using the risk scoring system using FLC ratio, serum M spike, marrow plasma cell% and presence of high risk FISH were enrolled provided they had adequate marrow and organ function. Patients with significant comorbidities such as heart disease were excluded from the trial. Treatment consisted of three phases: induction, consolidation and maintenance. Patients received carfilzomib (36 mg/m2 twice weekly or as per updated protocol 56mg/m2 weekly for 2 weeks), lenalidomide (25 mg daily for three weeks), daratumumab (weekly for 8 doses, every other week for 16 weeks) and dexamethasone 40 mg weekly, in 4 week cycles for 6 cycles as part of induction, the same regimen was administered with daratumumab every 4 weeks and dexamethasone 20 mg weekly for another 6 cycles for consolidation. This was followed by 12 cycles of maintenance therapy with lenalidomide (10 mg daily for three weeks), daratumumab (day 1 every other cycle) of a 4-week cycle. Appropriate antiviral, and thrombosis prophylaxis were mandated. The primary endpoint of this trial is the rate of confirmed sCR as best response across all cycles of treatment. We plan to accrue 83 patients to this trial with one-stage binomial trial design to test the null hypothesis that the true success (sCR) proportion is at most 65% and the alternate hypothesis of 80%. Results: Forty-six patients have been accrued to the trial as of July 14, 2020. The median age of the study population is 63 years (range 47 - 76); 70% are male. Overall, 2% have completed the maintenance, 50% have completed the consolidation, 80% have completed the induction and 15% are in the induction phase; only two patients have gone off treatment. The reasons for going off treatment were patient preference. At least one patient needed a dose modification for each drug; 17%, 2%, 13% and 7% required dose reductions for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively. The relative median dose intensity for the drugs were 85%, 92%, 80% and 98% for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively across the delivered cycles. The adverse events seen in at least 5% of the patients are as shown in the figure. A grade 3 or higher AE was seen in 52% of patients. There were no treatment related deaths observed. Response rate and depth have been as expected for this regimen in myeloma and analysis is pending completed accrual. Figure 1 Disclosures Kumar: Adaptive Biotechnologies: Consultancy; Sanofi: Research Funding; Cellectar: Other; Genecentrix: Consultancy; Novartis: Research Funding; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Carsgen: Other, Research Funding. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Dhakal:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Other: AdvIsory Board, Research Funding; Janssen: Consultancy, Other: Advisory Board, Research Funding; Takeda: Consultancy, Other: Advisory Board; GSK: Consultancy, Research Funding, Speakers Bureau; Sanofi: Research Funding. Abonour:Celgene: Consultancy; Janssen: Honoraria, Research Funding; Takeda: Consultancy; BMS: Consultancy, Research Funding. Rosenbaum:Celgene: Honoraria; Akcea: Honoraria; Amgen: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Research Funding. Bensinger:GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Bhutani:Prothena: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Janssen: Other: Clinical Trial Funding to Institute; BMS: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Takeda: Other: Clinical trial funding to institute, Speakers Bureau. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

scholarly journals THU0036 FIRST-IN-HUMAN TRIAL OF BCMA-CD19 COMPOUND CAR IN THE TREATMENT OF AUTOANTIBODY MEDIATED DISORDERS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 231.1-231
Author(s):  
F. Liu ◽  
H. Zhang ◽  
X. Wang ◽  
J. Feng ◽  
Y. Cao ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
B Cells ◽  
Plasma Cells ◽  
Phase 1 ◽  
Human Clinical Trial ◽  
Hla Antibodies ◽  
Time Points ◽  
Car T ◽  
Reh Cells

Background:Donor-specific anti-HLA antibodies (DSAs) are antibodies in the recipient directed against donor class I/II HLA antigens. The existence of DSAs before allogenic hematopoietic stem cell transplantation (AHSCT) are known to cause primary graft failure. Currently there’s no established method of DSA desensitization due to the long half-life of plasma cells.Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease involving in multiple organ systems mediated by numerous autoantibodies. Recent results have shown that depletion of B cells by CD19 CAR-T cells effectively reversed some manifestations in two SLE mouse models. However, plasma cells could be spared with single CD19 CAR-T cells, and peripheral circulating anti-DNA IgG and IgM autoantibodies remain elevated or increased in treated mice.Objectives:We present the efficacy of BCMA-CD19 compound CAR (cCAR), which target on antibody- producing “root”, both B cells and plasma cells in preclinical study and in our first-in-human phase 1 clinical trial.Methods:We constructed a BCMA-CD19 cCAR composed of a complete BCMA-CAR fused to a complete CD19 CAR, separated by a self-cleaving P2A peptide. We assessed the functional activity of cCAR in co-culture assay with multiple cell lines. We also verified cCAR efficacy with two mouse models, injected with either BCMA-expressing MM.1S cells or CD19-expressing REH cells. In our phase 1 clinical trial, we enrolled patients with hematologic malignancies with antibody mediated disorders.Results:BCMA-CD19 cCAR exhibited robust cytotoxic activity against the K562 cells engineered to express either CD19 or BCMA in co-culture assays, indicating the ability of each complete CAR domain to specifically lyse target cells. In mouse model study, cCAR-T cells were able to eliminate tumor cells in mice injected with MM.1S cells and REH cells, indicating that both BCMA and CD19 are specifically and equally lysing B cells and plasma cells in vivo, making BCMA-CD19 cCAR a candidate for clinical use.In our first-in-human clinical trial, the first case is a 48-year-old female patient having resistant B-ALL with high DSA titers. She exhibited complete remission of B-ALL at day 14 post-CAR T treatment. MFI of DSA dropped from 7800 to 1400 at 8 weeks post cCAR treatment, the reduction percentage was approximately 80% (Figure 1). The patient had no CRS, and no neurotoxicity was observed.Figure 1.1. A) MFI of DSA and other HLA antibodies before and at different time points after cCAR T infusion. B) the percent reduction post-transfusion of cCAR T cells at different time points.The second case is a 41-year-old female patient having a refractory diffuse large B cell lymphoma with bone marrow (BM) involvement. Furthermore, she has a 20 years of SLE, with manifestation of fever dependent of corticosteroids. On day 28 after cCAR treatment, PET/CT scan showed CR, and BM turned negative. In addition, she is independent of steroids, has no fever and other manifestations, C3/C4 are within normal ranges, and all the ANA dropped significantly, especially the nuclear type ANA, which turned from> 1:1000 to be negative at day 64. She had Grade 1 CRS but with no neurotoxicity observed. The absence of B cells and plasma cells persisted more than 5 months post CAR therapy.Conclusion:Our first in human clinical trial on BCMA-CD19 cCAR demonstrated profound efficacy in reducing DSA levels in an AHSCT candidate and ANA titer in a SLE patient. There was strong clinical evidence of depletion of antibody-producing roots, B-cells and plasma cells in both patients. Our results further suggested that BCMA-CD19 cCAR has the potential to benefit patients receiving solid organ transplants or those with other antibody-mediated diseases.Figure 2.Reduction of different type of ANA titer at different time points.Acknowledgments:patients and their familiesDisclosure of Interests:Fang liu: None declared, Hongyu Zhang: None declared, Xiao Wang: None declared, Jia Feng: None declared, Yuanzhen cao Employee of: Employee of iCell Gene Therapeutics LLC, Yi Su: None declared, Masayuki Wada Employee of: employee of iCell Gene Therapeutics LLC, Yu Ma Employee of: employee of iCAR Bio Therapeutics Ltd, Yupo Ma Shareholder of: shareholder of iCell Gene Therapeutics LLC

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